The proposed projects focus upon questions stemming from recent findings in our laboratory: (1) that a second site of lipoprotein particles (in GERL and the lysosomes which apparently form from it) is present in hepatocytes of normal rats; (2) that the fatty liver induced by a semisynthetic diet containing orotic acid (OA) can be reversed by adding clofibrate to the OA diet; and (3) that a fatty liver can be induced quickly by feeding a semisynthetic diet rich in sucrose to the homozygous mutant ("fatty") Zucker rat. The roles of GERL, a hydrolase-rich organelle, and related lysosomes, and of the Golgi apparatus, in secretion, interconversions and degradation of lipoproteins will be investigated, using: (a) ultrastructural cytochemical methods; (b) ultrastructural immunochemistry; and (c) isolation from liver homogenates of two fractions, one enriched in Golgi apparatus elements, the other in GERL elements. Ultrastructural immunocytochemistry will be used to study the secretory pathway of albumin during induction of fatty liver by OA when the Golgi apparatus no longer forms secretory vacuoles containing very low density lipoproteins (VLDL). Similar studies will be performed on livers of rats treated by 4-aminopyrazolopyrimidine, which also results in the disappearance of VLDL from the serum. The questions to be studied with obese Zucker rats include: (1) will fibrosis and cirrhosis develop in rats with fatty livers by prolonged feeding of the sucrose-enriched diet? (2) How do the larger lipoprotein particles present in the Golgi apparatus and GERL of the fatty liver differ from normal VLDL particles by ultrastructural, biochemical and immunochemical parameters? (3) Can the fatty liver be reversed by returning the rats to normal diet or by feeding them clofibrate? (4) will dietary orotic acid prevent and reverse the fatty livers induced by the sucrose-enriched diet? And (5) what effects will either dietary cholesterol or dietary ethanol have?